Hormone resistance is a particular problem in cancers such as prostate cancer and breast cancer.
Androgens, acting via androgen receptors, are essential for normal growth and function of the prostate gland and have been implicated in the progression of prostate cancer. Selective androgen receptor modulators (SARMs)—drugs intended to inhibit the activity of androgen receptors—are therefore standard treatment for prostate cancer. However, prostate cancers often become resistant to such treatment. A similar phenomenon can also occur in breast cancers treated with drugs that target the hormone receptor for estrogen.
A. Breast Cancer
Breast cancer is the most prevalent form of cancer among women in the United States and second leading cause of cancer related deaths (Jemal et al., 2006). According to 2006 cancer statistics, approximately 40,000 women are expected to die from breast cancer in the US (Jemal et al., 2006). In the year 2003, although a marked 7% decrease in the incidence of breast cancer was reported, this decrease mainly was associated with estrogen receptor positive (ER+) breast cancers (Ravdin et al., 2006). Estrogen receptor-negative (ER−) breast cancer still is essentially incurable and aggressive. Although, breast cancer treatment has undergone significant improvement, resistance develops to almost all forms of cancer therapy. Additionally, there has been little improvement in the treatment of ER− breast cancer. The high prevalence of breast cancer and development of resistance to effective treatments provides a strong stimulus for the development of additional, targeted therapies with minimal toxicity.
Hormone resistance is a particular problem in cancers such as breast cancer. The antiestrogen tamoxifen, intended to inhibit the activity of estrogen receptor, is standard treatment for breast cancer. However, breast cancers often become resistant to such treatment.
The knowledge that estrogens contribute a pivotal role in development of breast cancer has been exploited clinically by the development of endocrine agents, predominantly by estrogen withdrawal or antagonism (Jordan et al., 2007). Antiestrogen tamoxifen has been used to treat breast cancer for a number of years now. More recently, AIs such as letrozole and anastrozole have surpassed the beneficial effects of tamoxifen and are now being used in the clinic as the first line treatment for hormone dependent post-menopausal breast cancer (Goss et al., 2005; Goss et al., 2002). AEs/AIs are currently used for postmenopausal ER positive breast cancer agents (Brodie, 1990; Baum, 2002; Baum et al., 2002). The clinical use of these agents is limited by development of resistance and the presence of ER− cancer phenotype. Loss of AE/AI sensitivity has been associated with lack of ER expression.
B. Prostate Cancer
Prostate cancer is the most commonly diagnosed cancer in North American men and it is estimated that there are over 300,000 newly diagnosed cases each year (Landis, et al., 1998; Shibata, et al., 1998). The incidence and mortality rates from prostate cancer are increasing and this is due, in part, to an increasingly aging population and the higher incidence of this disease in older men (Gao et al., 1997; Chiarodo, 1991). Both benign prostatic hypertrophy (BPH) and prostate cancer are decreased or not detected in eunuchs and are linked not only to advancing age but the presence of testes and androgen function (Gao et al., 1997; Chiarodo, 1991; Sakti and Crawford, 1993).
Early prostate cancer tends to be androgen-dependent and requires expression of a functional androgen receptor (AR), whereas later stage tumors progress to androgen-independence which in some cases is correlated with loss of AR function (Cheng et al., 1993). Interestingly, the progression from early stage hormone-dependent to latter stage hormone-independence in prostate cancer in men is also observed for breast cancer in women where estrogen-responsiveness undergoes a similar pattern of change in women with early or late stage disease (Hopp and Fuqua, 1999; Fuqua et al., 1995).
Prostate cancer therapy is dependent on the stage of the tumor and AR expression. Early stage androgen-responsive prostate cancers can be treated by castration or with antiandrogens or drugs that block androgen-induced responses including steroidal antiandrogens (cyproterone), LHRH analogs, nonsteroidal antiandrogens (flutamide, nilutamide, bicalutamide), and the potent estrogenic drug diethylstilbestrol (reviewed in (Sadar et al., 1999; Klotz, 2000; Morris et al., 2000; Boccardo, 2000). In addition, there are several possible novel strategies for treatment of prostate cancer and other tumor-types and these include targeting of critical genes involved in tumor cell growth and metastasis (e.g., antiangiogenic drugs, antisense therapy) (Boasberg et al., 1997; Knox et al., 1998; 1998; Yamaoka et al., 1993; Folkman, 1995; Folkman, 1971). Ligands for nuclear receptors (NR) are also being developed for treatment of prostate cancer through inhibitory NR-AR crosstalk that involves various ligands or drugs that bind the retinoid acid/X-receptors (retinoids), vitamin D receptor (calcitrol), and peroxisome proliferator activate receptor γ (trogilatazone) (Dorai et al., 1997; Pienta et al., 1993; Pollard et al., 1991; Kelly et al., 1996; Miller et al., 1992; Miller et al., 1995; Peehl et al., 1994; Gross et al., 1998; Kubota et al., 1998; Tontonoz et al., 1997; Tontonoz et al., 1994; Smith et al., 1999).
The present invention is the first to use a combination of hormonal therapy and histone deacetylase inhibitors to treat hormone resistant cancers.